An elevated level of the phosphate regulating hormone fibroblast growth factor 23 (FGF23) is an independent risk factor for cardiovascular disease (CVD) and mortality across the spectrum of chronic kidney disease (CKD). Elevated FGF23 contributes directly to the pathogenesis of left ventricular hypertrophy, suggesting one potential mechanism for the high risk of CVD and death that is attributable to elevated FGF23. Preliminary data that demonstrate that elevated FGF23 is a powerful risk factor for congestive heart failure confirms the clinical relevance of FGF23-mediated LVH. Thus, data generated during the first 4 years of support under this award established elevated FGF23 as a novel biomarker and mechanism of adverse outcomes in CKD, and thus, novel therapeutic target. Additional work from our group was also the first to suggest a survival benefit of active vitamin D therapy in ESRD. However, active vitamin D raises FGF23, which might be expected to accelerate mortality. Reconciling this potential paradox is a central theme of this application. Based on preliminary data, we hypothesize that vitamin D may attenuate cardiac toxicity of FGF23 despite raising FGF23 levels, and that CKD patients' variable FGF23 response to active vitamin D, ranging from minimal to large increases, modifies their CVD risk and survival experience. In Aim 1, we will test the hypothesis that the magnitude of change in FGF23 in response to active vitamin D therapy modulates risk of mortality in a large prospective cohort of incident hemodialysis patients. In Aim 2, we will analyze FGF23 in a secondary analysis of a recently completed randomized trial of active vitamin D versus placebo in CKD stage 3-4 patients to test the hypothesis that baseline and follow-up FGF23 levels modify the cardiac structural and functional response to active vitamin D therapy. Previous studies suggest that non-calcium based phosphate binders lower FGF23, but there have been no placebo-controlled studies >2 weeks duration, and no studies examined the impact of FGF23 reduction on intermediate measures of CVD risk in CKD stage 3-4 patients with normal serum phosphate. Furthermore, no studies investigated the utility of combining phosphate binders with active vitamin D to potentially maximize their dual benefits on mineral metabolism and CVD. In Aim 3, we will conduct a one- year, placebo-controlled, 2 x 2 factorial, randomized study of CKD stage 3-4 patients to test the effects of active vitamin D and phosphate binders alone and in combination on FGF23, other mineral metabolites, and a comprehensive set of intermediate measures of CVD risk. Extensive preliminary data support our hypotheses, and our research team has the requisite expertise in FGF23, vitamin D, observational cohorts, and randomized studies with repeated measures to successfully complete these Aims. Renewed support will enable us to generate data that are critical for the rational design of larger trials in the futureand thereby support our long- term goal of translating FGF23 research into meaningful improvements in the management of CKD.